Mutational order and epistasis determine the consequences ofFBXW7mutations during colorectal cancer evolution

Abstract

AbstractSomatic driver mutations, in genes such asFBXW7,have been discovered in phenotypically normal colonic tissue, however their role in cancer initiation remains elusive. Here, using patient-derived human colon organoids as models of early tumour evolution we investigate the consequences ofFBXW7mutations in normal and gene-edited organoids. We observed thatFBXW7mutations exert an epistatic effect where the transcriptional consequences of the mutation are dependent on the background mutational makeup of the cell. Specifically, we found the timing of acquiring anFBXW7mutation relative toAPCmutation, led to profound differences. WhenFBXW7was mutated beforeAPC, repression of theAPCtranscriptional response and maintenance of near-normal cell state was seen. However, whenAPCwas mutated beforeFBXW7, cells acquired classic cancer-stem cell features. Single-cell RNA sequencing revealed thatFBXW7mutations in normal tissue also function by subtly reordering stem cell hierarchies and priming a fetal/regenerative phenotype through upregulation of YAP/TAZ signaling. Further analysis using transposase-accessible chromatin sequencing found this cellular plasticity was driven by changes in the chromatin accessibility of 36 transcriptional start site regions associated with TEAD1/TEAD2 motifs, which in turn upregulated YAP. Taken together, we demonstrate a critical role ofFBXW7mutations in preventing the initiation of colorectal cancer, and provide exemplar evidence for the importance of epistasis and mutational order in cancer biology.